An oral triple pill-based cocktail effectively controls acute myeloid leukemia with high translation

Abstract Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted-therapies aimed at reversing this hallmark, but most show only modest efficacy. Here we report a single oral pill containing low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms, that can effectively control AML. The cocktail comprises of oncogenic translation inhibitor Homoharringtonine (HHT), drug efflux pump P-gpi Encequidar (ENC) and anti-apoptotic protein Bcl-2i Venetoclax (VEN). Mechanically, the cocktail potently kills both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, we for the first time develop an oral triple pill-based cocktail with high efficacy, safety, simplicity for the AML patients, and provide proof of concept that a single pill containing triple combination cocktail is a promising avenue for AML therapy.